Abstract

The prevalence of atrial fibrillation (AF) is related to age and is projected to rise exponentially as the population ages and the prevalence of cardiovascular risk factors increases. The risk of ischemic stroke is significantly increased in AF patients, and there is evidence of a graded increased risk of stroke associated with advancing age. Oral anticoagulation (OAC) is far more effective than antiplatelet agents at reducing stroke risk in patients with AF. Therefore, increasing numbers of elderly patients are candidates for, and could benefit from, the use of anticoagulants. However, elderly people with AF are less likely to receive OAC therapy. This is mainly due to concerns about a higher risk of OAC-associated hemorrhage in the elderly population. Until recently, older patients were under-represented in randomized controlled trials of OAC versus placebo or antiplatelet therapy, and therefore the evidence base for the value of OAC in the elderly population was not known. However, analyses of the available trial data indicate that the expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. An important caveat with warfarin treatment is maintenance of a therapeutic international normalized ratio, regardless of the age of the patient, where time in therapeutic range should be ≥65%. Therefore, age alone should not prevent prescription of OAC in elderly patients, given an appropriate stroke and bleeding risk stratification.

Atrial fibrillation (AF) is a common cardiac arrhythmia that confers substantial mortality and morbidity from stroke, thromboembolism, and heart failure, and a significant impairment of quality of life (1,2). The prevalence of AF increases markedly with older age (3,4): about 5% of people over 65 years and 10% of people age ≥80 years suffer from AF (4). The lifetime risk of AF is approximately 1 in 4 among people age 40 years and older (2,5). AF is more prevalent in men than in women, although the absolute number of women and men with AF is similar, given that women outnumber men in the older age groups (6). The prevalence of AF is projected to rise exponentially as the population ages and the prevalence of cardiovascular risk factors increases (4).

AF is a major risk factor for stroke, increasing the risk of ischemic stroke by approximately 5-fold (6), with approximately 15% of all strokes in the U.S. being attributable to AF (6). Further, age is also a risk factor for stroke, with the lifetime probability of suffering a stroke increasing steadily with age, from 5.9% at 55 to 59 years, to 22.3% at 80 to 84 years in men, and from 3.0% to 23.9% over this age range in women (1). Therefore, the combination of increasing age and AF means that stroke prevention in elderly people with AF is paramount.

The objective of this systematic review is to provide an overview of published studies that have examined the relation between age and stroke/thromboembolism in AF. We appreciate that perioperative AF is also an important predictor of post-operative stroke, thromboembolism, and mortality, as highlighted in various reviews (7–9), but the focus of this paper will be thromboprophylaxis in the nonsurgical setting, and more on the outpatient nonacute clinical setting.

Age and Risk of Stroke in Studies

The importance of age as a risk factor for stroke in AF populations has been specifically evaluated in 17 studies (Table 1)examining the independent risk associated with age, either as a continuous variable (1,10–12) or incrementally by decade (13–21), or by employing an arbitrary cutoff (e.g., >75 years) (22–25). Twelve studies found increasing age to have an independent effect on the stroke risk (1,10,11,13–17,21–23,25), whereas 5 studies failed to find such an association (12,18–20,24).

Risk of Stroke/Thromboembolism and Major Bleeding by Antithrombotic Therapy in Randomized Controlled Trials and Cohort Studies

Being age 65 years or older was associated with a 3-fold increased risk of stroke (RR: 3.3, 95% CI: 1.92 to 5.81) in an observational study (22), with the Framingham study demonstrating that age (per decade) was independently associated with stroke, with a RR of 1.32 (95% CI: 1.02 to 1.76) (15). Among the 4 studies that evaluated thresholds of age to define age-related stroke risk (22–25), only 1 (24) did not find that being >70 years of age was a significant stroke risk factor. In this study, as in AFASAK I (12), hypertension—which is a well-known risk factor for stroke—also failed to emerge as an independent risk factor for stroke in AF (24).

Therefore, the balance of evidence suggests that age is an independent risk for stroke, with the magnitude of risk varying dependent on whether an incremental risk per decade or an age cutoff is employed (Table 2). There is a steep increase in the lifetime incidence of stroke with age both in men and women. The risk starts to rise at age 55 to 59 years from 5.9% in men and 3.0% in women to 11.0% and 7.2%, respectively, in the next decade, reaching an incidence of 22.3% and 23.9% in the 80- to 84-year-old group (1). Studies that have dichotomized age suggest a 1.4-fold increased risk of stroke per decade (13).

Risk Stratification Schemes

The absolute risk of stroke varies widely among patients with AF and is dependent not only on chronological age, but also on existing comorbidities and other clinical features. Indeed, multiple stroke risk stratification schemes for AF patients have been proposed (42) that vary substantially in complexity and incorporate different combinations of clinical and echocardiographic parameters. However, at the core of all the existing and most frequently employed schemes are 3 key features that have been independently and consistently associated with stroke in AF patients: advancing age (1,10–25), previous stroke or transient ischemic attack (TIA) (13,15–18,43–48), and hypertension (13,16,17,43–48). Other predictors of stroke among AF patients include diabetes (13,15–17,44–48), heart failure (43–47,49), left ventricular systolic dysfunction (17,43–47), systolic blood pressure (15,16,18,43,46,48), and coronary artery disease (44,46,48). Female sex is also emerging as a recognized, independent risk factor for stroke and thromboembolism (15,16,43,49,50).

Among trial-derived age cutoffs, age ≥75 years is the most widely used. Age >75 years is considered a high-risk factor for stroke in AF patients in the AF Investigators analysis (17) and in the American College of Chest Physicians guidelines (44,45). In the SPAF trial, age >75 years was also considered a high-risk factor for stroke in women and hypertensive patients (16). According to the American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC) Guidelines 2006 (47) and the CHADS2(congestive heart failure/hypertension/age/diabetes/prior stroke) score (49), age ≥75 years is an independent risk factor for stroke, whereas the NICE (National Institute for Health and Clinical Excellence) guidelines consider age ≥75 years as a high-risk factor for stroke in patients with diabetes, vascular disease, or hypertension (46).

However, the risk of AF increases as age rises since age is not a yes/no phenomenon (above or below a threshold). The stroke risk associated with AF increases dramatically from the age of 65 years onwards (3,4,22). For example, being age 72 years with 1 risk factor for stroke does not mean that your risk of stroke is appreciably less than that of a 75-year-old with 1 risk factor (except when working out stroke risk using risk stratification schemes). Indeed, the ACC/AHA/ESC 2006 guidelines (47) highlighted age 65 to 74 years as a “less validated or weaker risk factor for stroke.”

A refined version of the original CHADS2score and NICE schema, incorporating these “less well-validated or weaker stroke risk factors,” female sex, age 65 to 74 years, and vascular disease, and known as CHA2DS2-VASc score (51), was recently validated in the Euro Heart Survey on AF cohort. This refined stroke risk stratification system classifies all patients age ≥75 years and older as high risk. This is justified in part by the van Walraven et al. meta-analysis of RCTs (41), as well as the BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged) (52) and WASPO (Warfarin versus Aspirin for Stroke Prevention in Octogenarians with atrial fibrillation) (53) trials. Indeed, the cohort analysis by Gorin et al. (54) which shows that of the individual risk factors in an AF patient with a CHADS2score of 1, age ≥75 years carries the highest stroke risk, compared with heart failure, diabetes, or hypertension. Further, CHA2DS2-VASc also places greater emphasis on being age 65 to 74 years, with patients in this age category scoring 1 point for this risk factor alone (51).

The new CHA2DS2-VASc score (51) has sought to simplify the approach to anticoagulation in AF patients, suggesting oral anticoagulation (whether with warfarin or the new oral anticoagulants that avoid the disadvantages of warfarin, such as dabigatran—if approved) in moderate-high risk AF patients (i.e., a CHA2DS2-VASc score of ≥1), whereas those who are “truly low-risk” subjects (i.e., CHA2DS2-VASc score = 0), who could even be managed with no antithrombotic therapy (Table 3).

Antithrombotic Treatment and Stroke Risk in Elderly AF Patients

Even when there is evidence that age and AF independently increase stroke risk, elderly people with AF are less likely to receive oral anticoagulant therapy (OAC) despite standing to receive the greatest benefit from such treatment (55). Before the BAFTA trial (52), older patients (≥75 years) were significantly under-represented in RCTs of OAC versus placebo (mean age 69 years) (56) or antiplatelet therapy (mean [SD] age: 71.7 [8.8] years) (57), and therefore, the evidence base for the value of OAC in the elderly population was not known. The individual meta-analysis by van Walraven et al. (57) (conducted prior to the publication of BAFTA) suggested that OAC compared with aspirin reduced stroke (2.4 vs. 4.5 events per 100 patient-years; hazard ratio [HR]: 0.55; 95% CI: 0.43 to 0.71), but resulted in a 2-fold increase in bleeding risk.

However, the BAFTA trial (52) demonstrated that warfarin significantly reduces stroke risk in the elderly (mean [SD] age: 81.5 [4.2] years) compared with aspirin (1.8% vs. 3.8%, respectively; RR: 0.48, 95% CI: 0.28 to 0.80; p = 0.003). Another small RCT, of WASPO (53), also provides support for the use of warfarin over aspirin to reduce adverse events (composite end point of thromboembolism, major bleeding, and death) in elderly AF patients (>80 years of age).

The van Walraven et al. (57) meta-analysis based on data from 6 RCTs (mean age 71.7 years), also showed that OAC significantly decreases the risk of ischemic strokes (2.4%/yrs vs. 4.5%/yrs; HR: 0.55; 95% CI: 0.43 to 0.71) compared with aspirin for AF patients. More recently, these results have been confirmed by an updated meta-analysis of 11 RCTs, including BAFTA, which also demonstrated that OAC significantly reduced the risk of ischemic stroke compared with aspirin and placebo (OAC adjusted HR per decade increase: 0.36; 95% CI: 0.29 to 0.45; antiplatelets: 0.81; 95% CI: 0.72 to 0.90) (41). In this analysis, the relative benefit of OAC in preventing stroke was not significantly affected by increasing age, whereas the benefit of aspirin decreased significantly as patients aged. The recent study by Singer et al. (58) from the ATRIA (AnTicoagulation and Risk Factors in Atrial Fibrillation) cohort also showed a reduction in absolute stroke risk with warfarin: the benefit was greater in very elderly patients (age ≥85 years) and among those at high stroke risk.

Antithrombotic Treatment and Bleeding Risk in Elderly AF Patients

Physicians may be apprehensive about prescribing OAC to elderly patients, given concerns about a higher risk of OAC-associated hemorrhage (13,17,44,52,59,60) among older people. Intracranial hemorrhage (ICH) is the most feared and devastating complication of warfarin therapy (61). The risk of ICH is increased 2.5-fold among people age ≥85 years (61), although the absolute risk of warfarin-associated ICH in AF patients is relatively low at 0.2% per year (62). A recent meta-analysis of RCTs, including BAFTA, demonstrated that increasing age raises the risk of serious bleeding (HR: 1.61; 95% CI: 1.47 to 1.77) (41), although the risk of major hemorrhage was similar among patients receiving warfarin and aspirin (1.4% vs. 1.6%; RR: 0.87, 95% CI: 0.43 to 1.73).

Of the published bleeding risk stratification schema available, all include age as a risk factor for bleeding (63,64), but there is no consistency in the other risk factors included in these bleeding risk models. The most recently proposed risk schema is the HAS-BLED (HAS-BLED: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly [>65], Drugs/alcohol concomitantly) score (65) (Table 4),which could be used as a simple, easy assessment of bleeding risk in AF patients: thus, a score of ≥3 indicates high risk, and some caution and regular review of the patient is needed, following the initiation of antithrombotic therapy, whether with a vitamin K antagonist or aspirin.

The mechanism by which age is associated with major hemorrhage may be multifactorial (66,67) and can be broadly divided into treatment- and person-dependent reasons. High anticoagulation intensity and INR variability are risk factors for hemorrhage, with INR ≥3.5 associated with an almost 5-fold increased risk of major hemorrhage, especially among the elderly (age >80 years) (61,68).

Often, lower-intensity INR ranges are employed among elderly patients to prevent warfarin-associated hemorrhages. However, an INR <2.0 is not associated with a lower rate of ICH than standard INR targets (2.0 to 3.0) in the elderly (61,69) and should be avoided given the obvious associated increased risk of thromboembolic events at suboptimal INR levels (70). The risk of hemorrhagic events is also higher during the first 90 days of treatment, decreasing considerably thereafter (71), and the hazards related to warfarin seem to be greater in patients new to warfarin compared with warfarin-established patients before study entry (72).

Crucial to both bleeding and stroke rates is the quality of INR control, which is contingent on the level of INR surveillance and provision of OAC services. Recent studies have demonstrated that time in therapeutic range (TTR) needs to be at a minimum of 58% to derive benefit from OAC in an analysis from ACTIVE-W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) (73) and >71% outside of the trial setting (74). In real-life clinical practice, beneficial levels of TTR may be difficult to achieve. In a prospective observational study of 783 AF patients (median age 75 years, range 37 to 94 years), patients had a TTR of 71% (75), with no difference in TTR between patients age <80 and ≥80 years. Although being age ≥80 years was associated with a 2-fold increased risk of bleeding (75), the absolute rate of major bleeding of patients age >80 years is relatively low (rate: 2.5 %/yrs).

Other risk factors for major hemorrhage among AF patients have been identified, including prior stroke and gastrointestinal bleeding, hypertension, concomitant antiplatelet use, anemia, renal insufficiency, presence of cerebrovascular disease, and malignancy, all of which may be more common among elderly people (63,64). Polypharmacy (with the possibility of interacting drugs) and insufficient education about anticoagulation also have been linked to hemorrhage (71). In addition, cognitive dysfunction, functional impairments, and increased fall risk, further complicate OAC management in elderly patients (13).

Net Clinical Benefit

When prescribing OAC therapy for AF patients, we must consider the net clinical benefit of such treatment. Two recent analyses have addressed this issue. In an analysis of the ATRIA cohort (58), the adjusted net clinical benefit of warfarin (annualized rate of thromboembolic events minus the annualized ICH rate [weighted]) for the overall cohort was 0.68% per year (95% CI: 0.34% to 0.87%). The benefit from anticoagulation was greater for those age 85 years or older (2.34% per year [95% CI: 1.29% to 3.30%]) and for patients with a history of ischemic stroke (2.48% per year [95% CI: 0.75% to 4.22%]). Importantly, the TTR in the ATRIA cohort was good at 65% (54).

The van Walraven et al. (41) meta-analysis of 11 RCTs demonstrated an age-related increase in both ischemic stroke and major bleeding risk, with OAC and antiplatelet therapy significantly reducing the stroke risk (RR: 0.36; 95% CI: 0.29 to 0.45, and 0.81; 95% CI: 0.75 to 0.88, respectively), with OAC increasing the risk of serious bleeding (RR: 1.56; 95% CI: 1.03 to 2.37) compared with placebo (41). There was an interaction between patient age and stroke prevention. Antiplatelet therapy offered no additional benefit in octogenarians over placebo. However, OAC therapy continued to offer significant protection against stroke with increasing age, although the benefit was attenuated. There was no interaction between age and OAC or antiplatelet therapy for serious bleeding. Therefore, elderly AF patients will receive a greater net clinical benefit from OAC therapy as they face the greatest stroke risk. The results of this meta-analysis (41) differ from their earlier meta-analysis (57), which suggested that the relative benefit of OAC over antiplatelet drugs may decrease as patients age. The discrepancy in these findings may result from the inclusion of 5 additional studies, increasing the number of ischemic stroke events, raising the number of elderly patients (n = 1,359, age >75 years), and employing age as a continuous variable in the most recent statistical analyses (41) compared with the dichotomization of a continuous variable, comparing age <75 and ≥75 years (57).

New Oral Antithrombotic Medications

Although the advent of newer oral antithrombotic agents on the horizon will hopefully offer greater therapeutic choice for stroke prophylaxis in AF patients, with a more stable pharmacokinetic profile and fewer inherent problems than warfarin, there will still remain the need to evaluate net clinical benefit.

Although these data are extremely encouraging, more data on long-term safety are awaited, given there was an increased risk of dyspepsia, gastrointestinal major hemorrhage, and myocardial infarction with dabigatran compared with warfarin. Other data from another class of novel oral anticoagulants, the oral factor Xa inhibitors, are awaited.

Conclusions

Physicians may be apprehensive about prescribing OAC to elderly patients, given concerns about a higher risk of OAC-associated hemorrhage (63,68,7,75). However, age alone should not prevent prescription of OAC in elderly patients, given the potential greater net clinical benefit among such patients (41,58). Appropriate stroke and bleeding risk stratification and choice of antithrombotic therapy are essential. Once OAC is initiated, good INR control (at least 65% TTR) and the provision of a health care infrastructure to support such INR therapeutic targets are crucial to prevent warfarin-associated complications.

Footnotes

Prof. Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, Aryx, Portola, Biotronic, and Boehringer, and has been on the Speakers' Bureau for Bayer, Boehringer, and Sanofi. Dr. Lane is in receipt of an investigator-initiated educational grant from Bayer Healthcare, and has received industry-funded sponsorship for travel to cardiology conferences. All other authors have reported that they do not have any relationships to disclose.

(2006) Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation114:119–125, (erratum in Circulation 2006;114:e498).

(2006) ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol48:854–906.

(2007) Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birminigham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomized controlled trial. Lancet370:493–503.

(2008) Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation118:2029–2037.

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